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  Accepted Manuscript Synthesis, spectroscopic characterizations, enzyme inhibition, molecular dockingstudy and DFT calculations of new Schiff bases of sulfa drugsSaliha Alyar, Tülin Şen, Cihan Şen, Hamit Alyar, Şevki Adem, Ümmühan ÖzmenÖzdemir PII:S0022-2860(19)30254-6DOI:https://doi.org/10.1016/j.molstruc.2019.03.002Reference:MOLSTR 26271To appear in: Journal of Molecular Structure  Received Date:23 November 2018Revised Date:5 February 2019Accepted Date:1 March 2019Please cite this article as: S. Alyar, Tü. Şen, C. Şen, H. Alyar, Ş. Adem, Üü.Ö. Özdemir, Synthesis,spectroscopic characterizations, enzyme inhibition, molecular docking study and DFT calculations of new Schiff bases of sulfa drugs, Journal of Molecular Structure  (2019), doi: https://doi.org/10.1016/ j.molstruc.2019.03.002.This is a PDF file of an unedited manuscript that has been accepted for publication. As a service toour customers we are providing this early version of the manuscript. The manuscript will undergocopyediting, typesetting, and review of the resulting proof before it is published in its final form. Pleasenote that during the production process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain.  A CCEPTED MANUSCRIPT New Schiff bases were synthesized (Z)-4-((4-(diethylamino)benzylidene)amino)-N-(3,4-dimethylisoxazol-5-yl)benzenesulfonamide (L1) and   (Z)-4-((4-(dimethylamino)benzylidene)amino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (L2)   derived from sulfamethoxazole (S1)/sulfisoxazole (S2) and substituted salicylaldehyde. Evaluated the effects of compounds (L1/L2) on eight enzyme activities (Tyrosinase, cholesterol esterase, α -amylase, lipase, carbonic anhydrase II, acetylcholine esterase (AChE) and butyrylcholinesterase enzymes). Also, To comprehend the binding interactions between the inhibitors and enzymes with low IC 50  values, molecular docking studies of compounds were performed for cholesterol esterase, and tyrosinase.  A CCEPTED MANUSCRIPT Synthesis, spectroscopic characterizations, enzyme inhibition, molecular docking study and DFT calculations of new Schiff bases of Sulfa drugs. Saliha Alyar 1 ✉✉✉✉ , Tülin Ş en 1 , Cihan Ş en 1 , Hamit Alyar 2 ,   Ş evki Adem 1 , Ümmühan Özmen Özdemir 3   1  Department of Chemistry, Faculty of Science, Karatekin University, 18100 Çankırı, Turkey 2  Department of Physics, Faculty of Science, Karatekin University, 18100 Çankırı, Turkey 3  Department of Chemistry, Faculty of Science, Gazi University, 06500, Ankara, Turkey Email:saliha@karatekin.edu.tr ABSTRACT New Schiff bases were synthesized (Z)-4-((4-(diethylamino)benzylidene)amino)-N-(3,4-dimethylisoxazol-5-yl)benzenesulfonamide (L1) and   (Z)-4-((4-(dimethylamino)benzylidene) amino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (L2)   derived from sulfamethoxazole (S1)/sulfisoxazole (S2) and substituted salicylaldehyde. The synthesized compounds were characterized by FT-IR, 1 H- 13 C NMR, LC-MS. We evaluated the effects of compounds on eight enzyme activities by spectrophotometric assays at final concentrations of 0.5-5 µg. L1  acted as an inhibitor on cholesterol esterase, tyrosinase and α -amylase activities with IC 50  values 38, 38 and 173 µM. Tyrosinase, α -glucosidase, cholesterol esterase, and α -amylase enzymes were inhibited by L2  with IC 50  values 24, 46, 63, and 231 µM. To comprehend the binding interactions between the inhibitors and enzymes with low IC 50  values, molecular docking studies of compounds were performed for cholesterol esterase and tyrosinase. Finally, molecular docking was performed to determine the probable binding mode of the designed compounds into the active site of enzymes. DFT calculations were carried out at the B3LYP levels of theory with 6-311G ++ (d, p) basis set for compounds.  A CCEPTED MANUSCRIPT Keywords:  Sulfisoxazole, Sulfamethoxazole, enzyme inhibition, molecular docking 1.   Introduction  The nutrients taken on the diet are broken down by pancreatic enzymes and made ready to be absorbed in the small intestine. Various diseases are prevented or treated via the inhibition of these digestive enzymes. Diabetes mellitus (DM) is a significant health problem of today and tomorrow [1]. The high-carbohydrate diets contribute the disease significantly. The carbohydrates taken from the diet are broken down to glucose by α -amylase and α -glucosidase enzymes and ready for absorption [2]. They are an essential target in the treatment of type 2 diabetes because the inhibition of these enzymes delays the absorption of glucose [3]. Cholesterol is known to cause a variety of health problems such as heart attack, cardiac arrest, obesity, diabetes, atherosclerosis and stroke. Dietary cholesterol contributes significantly to serum cholesterol levels [4]. It has been reported that pancreatic cholesterol esterase (CEase, EC 3.1.1.13) plays an important role both in the release of dietary cholesterol and in the formation of micelles for transport [5, 6]. Its inhibition causes the level of serum cholesterol from the diet to drop at a reasonable rate. Therefore, it has been considered an important target in the treatment of cholesterol-related diseases. Pancreatic lipase (PL) is considered to be a successful target to treat or prevent obesity [7, 8]. Melanin produced by melanogenesis process in the melanocytes causes browning in human skin, eye, and hair. Since tyrosinase catalyzes the first and rate-limiting step of the melanin synthesis, its inhibitors are used in the cosmetics or skin lightening agents [9, 10]. Sulfonamides together with various pharmacological agents with antibacterial [11-13], insulin-releasing [14, 15], carbonic anhydrase inhibitory [16, 17], anti-inflammatory [18], antidiabetic [19, 20] and antitumor [21, 22] activities is an important class of drugs. With

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